e16538 Background: Pembrolizumab has demonstrated efficacy in improving disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in clear cell renal cell carcinoma (ccRCC) at high risk of recurrence. However, real-world evidence supporting its use in Chinese patients remains limited. This study evaluated the real-world effectiveness and safety of adjuvant pembrolizumab in a multicenter cohort. Methods: This multicenter retrospective study recruited 18–80-year-old patients with high-risk clear cell renal cell carcinoma (ccRCC). High-risk status was defined as either M0 disease with adverse pathological features (pT2 with grade 4/sarcomatoid differentiation, any pT3/T4, or any pT with N1) or M1 oligometastatic disease achieving no evidence of disease (NED) after complete resection. The treatment cohort included patients who received at least one cycle of adjuvant pembrolizumab and was 1:2 matched to an observation cohort via propensity score matching to achieve baseline balance. The primary endpoint was DFS; secondary endpoints included OS and treatment-related adverse events (TRAEs). Results: Between January 2023 and December 2025, 396 patients were enrolled, including 114 who received pembrolizumab and 282 managed with observation. Baseline imbalances in age, M stage, and nuclear grade were observed before matching. After matching, 90 patients in the pembrolizumab group and 161 in the observation group were analyzed, with well-balanced baseline characteristics. At the data cutoff (December 31, 2025), median follow-up was 13.1 months in the pembrolizumab group and 24.6 months in the observation group. Disease recurrence occurred in 6.7% (6/90) of patients receiving pembrolizumab compared with 22.4% (36/161) in the observation cohort. Median DFS was not reached in either group (HR 0.56, 95% CI 0.23–1.00). The 24-month DFS rate was 90.5% in the pembrolizumab group versus 73.2% in the observation group. TRAEs were reported in 50.8% of treated patients, predominantly grade 1-2. Grade 3 TRAEs occurred in 13.3% of patients, and grade 4 events were limited to two cases of immune-related myocarditis. The most common TRAEs included rash (21.3%), proteinuria (12.2%) and thyroid dysfunction (10.2%). Severe adverse events (SAEs) led to treatment discontinuation in 10.5% of patients, with hypothyroidism (3.5%), colitis (2.6%) and hypertransaminasemia (2.6%) as the most frequent events, and no treatment-related deaths were noted. Retrospective study design and short follow-up limit long-term outcome assessment. Conclusions: In this multicenter real-world Chinese cohort, adjuvant pembrolizumab was associated with improved DFS and a manageable safety profile in patients with high-risk ccRCC. Larger studies with longer follow-up are warranted to further validate these findings.

BACKGROUND:While emotional distress, encompassing anxiety and depression, has been associated with negative clinical outcomes, its impact across various clinical departments and general hospitals has been less explored. Previous studies with limited sample sizes have examined the effectiveness of specific treatments (e.g., antidepressants) rather than a systemic management strategy for outcome improvement in non-psychiatric inpatients. To enhance the understanding of the importance of addressing mental health care needs among non-psychiatric patients in general hospitals, this study retrospectively investigated the impacts of emotional distress and the effects of early detection and management of depression and anxiety on hospital length of stay (LOS) and rate of long LOS (LLOS, i.e., LOS >30 days) in a large sample of non-psychiatric inpatients. METHODS:This retrospective cohort study included 487,871 inpatients from 20 non-psychiatric departments of a general hospital. They were divided, according to whether they underwent a novel strategy to manage emotional distress which deployed the Huaxi Emotional Distress Index (HEI) for brief screening with grading psychological services (BS-GPS), into BS-GPS ( n = 178,883) and non-BS-GPS ( n = 308,988) cohorts. The LOS and rate of LLOS between the BS-GPS and non-BS-GPS cohorts and between subcohorts with and without clinically significant anxiety and/or depression (CSAD, i.e., HEI score ≥11 on admission to the hospital) in the BS-GPS cohort were compared using univariable analyses, multilevel analyses, and/or propensity score-matched analyses, respectively. RESULTS:The detection rate of CSAD in the BS-GPS cohort varied from 2.64% (95% confidence interval [CI]: 2.49%-2.81%) to 20.50% (95% CI: 19.43%-21.62%) across the 20 departments, with a average rate of 5.36%. Significant differences were observed in both the LOS and LLOS rates between the subcohorts with CSAD (12.7 days, 535/9590) and without CSAD (9.5 days, 3800/169,293) and between the BS-GPS (9.6 days, 4335/178,883) and non-BS-GPS (10.8 days, 11,483/308,988) cohorts. These differences remained significant after controlling for confounders using propensity score-matched comparisons. A multilevel analysis indicated that BS-GPS was negatively associated with both LOS and LLOS after controlling for sociodemographics and the departments of patient discharge and remained negatively associated with LLOS after controlling additionally for the year of patient discharge. CONCLUSION:Emotional distress significantly prolonged the LOS and increased the LLOS of non-psychiatric inpatients across most departments and general hospitals. These impacts were moderated by the implementation of BS-GPS. Thus, BS-GPS has the potential as an effective, resource-saving strategy for enhancing mental health care and optimizing medical resources in general hospitals.

With the aging of the population, the prevalence of osteoporosis and multimorbidity is increasing. Patients with osteoporosis often experience varying levels of emotional distress, including anxiety and depression. However, few studies have explored the patterns of multiple conditions and their impact on patients’ emotional distress. Here, we conducted a network analysis to explore the patterns of multimorbidities and their impact on emotional distress in 13,359 Chinese Han patients with osteoporosis. The results showed that multimorbidity was prevalent in Chinese patients with osteoporosis and increased with age, and was more frequent in males than in females, with the most common pattern of multimorbidity being osteoporosis and essential (primary) hypertension. Finally, we found that patients’ emotional distress increased with the number of multimorbidities, especially in female patients, and identified eight multimorbidities with high correlation to patients’ emotional distress.

Introduction: Nephron-sparing surgery is the recommended surgical management of T1 renal cell carcinoma (RCC). However, non-clear cell RCC (nccRCC) is heterogeneous and included many histological types. Therefore, the present study was performed to compare radical nephrectomy (RN) versus partial nephrectomy (PN) in nccRCC. Materials and methods: Within the Surveillance, Epidemiology, and End Results registry (2000-2019), the patients with nccRCC were identified. Kaplan-Meier survival curve and the log-rank test were conducted. Univariate analysis and multivariate Cox regression analysis were performed to explore the prognostic factors. Results: A total of 7575 patients with nccRCC were included, of which papillary RCC (n = 5219) is the major histology. Kaplan-Meier plots and log-rank tests showed that nccRCC patients who underwent RN had significantly worse overall survival (OS) and cancer-specific survival (CSS) than those who received PN (all P < 0.05). Multivariate analysis also revealed that RN was significantly associated with poor OS and CSS in nccRCC patients. Stratified by histological types, the multivariate analysis also revealed that RN was significantly associated with poor OS in papillary and chromophobe (all P < 0.05). Besides, the multivariable analysis indicated that RN was associated with poor CSS in papillary RCC (P < 0.05). For other histology, the patients who received RN had a comparable survival to those who received PN. Conclusion: For patients with T1 nccRCC, our findings revealed that PN was not inferior to RN in OS and CSS. PN may be also the preferred option for T1 nccRCC, but more prospective studies are required to validate this finding. (c) 2023 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Gangliosides are a large subfamily of glycosphingolipids that broadly exist in the nervous system and interact with signaling molecules in the lipid rafts. GD3 and GD2 are two types of disialogangliosides (GDs) that include two sialic acid residues. The expression of GD3 and GD2 in various cancers is mostly upregulated and is involved in tumor proliferation, invasion, metastasis, and immune responses. GD3 synthase (GD3S, ST8SiaI), a subclass of sialyltransferases, regulates the biosynthesis of GD3 and GD2. GD3S is also upregulated in most tumors and plays an important role in the development and progression of tumors. Many clinical trials targeting GD2 are ongoing and various immunotherapy studies targeting gangliosides and GD3S are gradually attracting much interest and attention. This review summarizes the function, molecular mechanisms, and ongoing clinical applications of GD3, GD2, and GD3S in abundant types of tumors, which aims to provide novel targets for future cancer therapy.

Identifying biomarkers to predict lapse of alcohol-dependence (AD) is essential for treatment and prevention strategies, but remains remarkably challenging. With an aim to identify neuroimaging features for predicting AD lapse, 66 male AD patients during early-abstinence (baseline) after hospitalized detoxification underwent resting-state functional magnetic resonance imaging and were then followed-up for 6 months. The relevance-vector-machine (RVM) analysis on baseline large-scale brain networks yielded an elegant model for differentiating relapsing patients (n = 38) from abstainers, with the area under the curve of 0.912 and the accuracy by leave-one-out cross-validation of 0.833. This model captured key information about neuro-connectome biomarkers for predicting AD lapse.

Alveolar echinococcosis (AE) is an important zoonotic tropical disease in China that affects people living in western endemic areas. The disease is prone to occur in the liver with a characteristic similar to slow-growing malignant tumors. We report a 31-year-old male patient with serious complication after hepatorrhaphy, who had presented with clinical manifestations of hepatapostema with infection. Ultrasound (US) and computer tomography (CT) are two important medical imaging modalities to diagnose hepatic AE. Based on the medical history, clinical findings, laboratorial and imaging results, the patient was misdiagnosed with hepatapostema. A series of subsequent treatments were ineffective. Finally, partial hepatectomy was performed, and postoperative pathological results confirmed hepatic AE. The patient has now recovered.

ObjectiveThe purpose of this study is to examine the association between a novel adiposity parameter, the weight-adjusted-waist index (WWI), and erectile dysfunction (ED). MethodsAccording to National Health and Nutrition Examination Survey (NHANES) 2001-2004, a total of 3884 participants were categorized as ED and non-ED individuals. WWI was calculated as waist circumference (WC, cm) divided by the square root of weight (kg). Weighted univariable and multivariable logistic regression models were conducted to assess the correlation between WWI and ED. Smooth curve fitting was utilized to examine the linear association. The receiver operating characteristic (ROC) curve and DeLong et al.'s test were applied to compare the area under curve (AUC) value and predictive power among WWI, body mass index (BMI), and WC for ED. ResultsWWI was positively related to ED with the full adjustment [odds ratio (OR)=1.75, 95% confidence interval (95% CI): 1.32-2.32, p=0.002]. After converting WWI to a categorical variable by quartiles (Q1-Q4), compared to Q1 the highest WWI quartile was linked to an obviously increased likelihood of ED (OR=2.78, 95% CI: 1.39-5.59. p=0.010). Subgroup analysis revealed the stability of the independent positive relationship between WWI and ED. It was shown that WWI had a stronger prediction for ED (AUC=0.745) than BMI (AUC=0.528) and WC (AUC=0.609). Sensitivity analysis was performed to verify the significantly positive connection between WWI and stricter ED (OR=2.00, 95% CI: 1.36-2.94, p=0.003). ConclusionAn elevated WWI was related to higher risks of ED in the United State adults, and a stronger predictive power of WWI for ED was observed than BMI and WC.

Background: Internet addiction (IA) is associated with adverse consequences, especially for younger people. Evidence indicates that IA is associated with depression, but no studies have yet investigated potential common vulnerability between them. Methods: IA (measured by the Young's 20-item Internet Addiction Test Scale) and depressive symptoms (measured by the Patient Health Questionnaire-9 Scale) among 12 043 undergraduates were surveyed at baseline and at a respective 12 month follow-up for each participant. Application of a cross-lagged panel model approach (CLPM) revealed an association between IA and depression after adjusting for demographic variables. Results: Rates of baseline IA and depression were 5.47% (95% CI: 5.07%, 5.88%) and 3.85% (95% CI: 3.51%, 4.20%), respectively; increasing to 9.47% (95% CI: 8.94%, 9.99%) and 5.58% (95% CI: 5.17%,5.99%), respectively, at follow-up. Rates of new-incidences of IA and depression over 12 months were 7.43% (95% CI: 6.95%, 7.91%) and 4.47% (95% CI: 4.09%, 4.84%), respectively. Models in the present analysis revealed that baseline depression had a significant net-predictive effect on follow-up IA, and baseline IA had a significant netpredictive effect on follow-up depression. Limitations: The follow-up survey response rate was moderate (54.69%) in this analysis of university students. Moreover, the IAT-20 scale did not allow differentiate between specific forms of Internet activity. Conclusions: Common vulnerability and bidirectional cross-causal effects may both contribute to the association between IA and depression, with common vulnerability likely playing a more significant role than cross-causal effects.

Background Smoking remains a highly significant preventable global public health problem. In this context, digital interventions offer great advantages in terms of a lack of biological side effects, possibility of automatic delivery, and consequent human resource savings relative to traditional interventions. Such interventions have been studied in randomized controlled trials (RCTs) but have not been systematically reviewed with the inclusion of text-based and multiplatform-based interventions. In addition, this area has not been evaluated from the perspective of the psychological theoretical basis of intervention. Objective The aim of this paper is to assess the efficiency of digital interventions in RCT studies of smoking cessation and to evaluate the effectiveness of the strategies used for digital interventions. Methods An electronic search of RCTs was conducted using PubMed, Embase, and the Cochrane Library by June 30, 2021. Eligible studies had to compare automated digital intervention (ADI) to the use of a self-help guideline or no intervention. Participants were current smokers (aged 16 years or older). As the main outcome, abstinence after endpoint was extracted from the studies. Systematic review and meta-analysis were conducted to assess the efficiency of ADIs. Metaregressions were conducted to assess the relationship between intervention theory and effectiveness. Results A total of 19 trials (15,472 participants) were included in the analysis. The overall abstinence rate (95% CI) at the endpoint was 17.8% (17.0-18.7). The overall risk ratio of the intervention group compared to the controls at the endpoint was 17.8% (17.0-18.7). Cochrane risk-of-bias tool for randomized trials (ROB 2) suggested that most of the studies had a low risk of bias (56.3%). Psychological theory–related constructs or predictors, which refer to other theory-based concepts (rather than only behavioral theory) such as craving or anxiety, are associated with effectiveness. Conclusions This study found that ADI had a clear positive effect compared to self-help guidelines or to no intervention, and effectiveness was associated with theory-related constructs or predictors. ADIs should be promoted by policy makers and clinical practitioners to address the huge gap between the need for smoking cessation and availability of traditional treatment resources. Possible increases in ADI efficiency may be achieved by optimally integrating psychotherapeutic theories and techniques. Trial Registration PROSPERO CRD42021256593; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=256593

BackgroundNaples prognostic score (NPS), a novel scoring system based on nutritional and inflammatory status, is associated with prognosis in several cancers. This study aimed to evaluate the prognostic significance of preoperative NPS in patients undergoing nephrectomy.Patients and MethodsThis study retrospectively analyzed patients with renal cell carcinoma (RCC) who underwent radical or partial nephrectomy between 2010 and 2013. The clinicopathological characteristics of patients stratified by preoperative NPS were compared. Survival analysis was performed using the Kaplan–Meier method and log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify independent prognostic factors. Receiver operating characteristic curves were used to evaluate prediction efficiency.ResultsA total of 638 patients with operable RCC were included. The high-NPS group (NPS group 2) was significantly associated with older age (P < 0.001), larger tumor size (P < 0.001), worse pathological T stage (P < 0.001), positive lymph node pathology (P = 0.002), higher tumor grade (P < 0.001), and greater tumor necrosis (P < 0.001). Multivariable analysis demonstrated that the high-NPS subgroup had significantly worse overall survival (OS) [hazard ratio (HR): 2.25, 95% confidence interval (CI): 1.45–3.50, P < 0.001] and progression-free survival (PFS) (HR: 2.26, 95% CI: 1.48–3.44, P < 0.001). Among several preoperative scoring systems, NPS had the strongest discriminatory power for predicting OS and PFS.ConclusionPreoperative NPS can serve as a simple novel risk stratification tool to optimize the prognosis of patients with operable RCC. Further prospective and large-scale studies are needed to validate our findings.

Clear-cell renal cell carcinoma (ccRCC) is one of the most common urological cancers. The tumor microenvironment plays an important role in tumor development. The present study was conducted to identify novel immune-related biomarkers. The differentially expressed genes were identified using the ESTIMATE algorithm base on GEO and TCGA databases. The Kaplan–Meier survival curve and univariate and multivariate analyses were performed. The association between ST8SIA1 and the immune system was explored. The gene set enrichment analysis (GSEA) and online databases were used for functional annotation. ST8SIA1 was identified as a potential prognostic gene. Elevated ST8SIA1 was observed in the tumor tissues compared with adjacent normal tissues and associated with higher T stage and advanced TNM stage (all p < 0.05). The mRNA and protein levels of ST8SIA1 in cancer tissues and cells are also upregulated. The Kaplan–Meier survival curve and univariate and multivariate analyses showed that higher expression of ST8SIA1 was associated with worse OS (all p < 0.05). ST8SIA1 expression levels were negatively correlated with tumor purity and positively associated with infiltrated immune cells and expression of immune checkpoint genes. Function analysis also revealed that ST8SIA1 was significantly associated with immune-related pathways. In conclusion, ST8SIA1 was identified as an immune-related gene and a potential target in ccRCC patients. Further relevant studies are required to validate our findings.

Adrenocortical carcinoma (ACC) is a rare endocrine tumor, and most cases present with hormone excess with poor prognosis. Our research aims to determine the clinical and biological significance of glucocorticoid receptor (GR) expression using large cohorts of ACC patients. Immunohistochemistry was used to assess the expression of GR in 78 ACC cases from the West China Hospital (WCH) cohort. RNA-seq data were retrieved from The Cancer Genome Atlas database (TCGA, n=79). Clinicopathological and follow-up data were obtained from two cohorts. The correlation between the GR gene and tumor immune status was estimated using TIMER and GEPIA2. Kaplan-Meier analysis was performed to identify the prognostic value of GR in ACC. In the WCH cohort, positive nuclear GR staining was identified in 90% of the primary ACC cases. Cortisol-secreting ACCs demonstrated significantly lower GR protein expression than did nonfunctioning tumors (P<0.001). This finding was validated by the mRNA data analysis of the TCGA cohort (P = 0.030). GR expression was found to be positively correlated with the immune cell infiltration level and immune-checkpoint-related gene expression in ACC. Survival comparison and multivariate analysis showed that GR expression is an independent prognostic predictor of disease-free survival and overall survival in ACC patients in both cohorts. Our findings suggest that low GR expression is significantly correlated with excess cortisol, immune signatures and poor survival in ACC patients. We propose that GR signaling may play an important role in ACC behavior and thus may be a therapeutic target, which deserves further research.

Introduction Insomnia is a major public health problem that determines the quality of life. Among the many causes of insomnia, psychological factors have an important influence on the process, duration of insomnia, help-seeking behavior, and treatment choice. Regarding medical treatment, zolpidem is always chosen to treat acute and transient insomnia due to its few side effects. Although some randomized controlled trials have verified its safety, zolpidem abuse and withdrawal reactions have been reported in recent years. Case report A 25-year-old unmarried man with a college degree who worked as a graphic designer was referred and admitted to the inpatient ward for a chief complaint of “alternative episodes of lowering and elevation of mood for 10 years, overdosage use of zolpidem for two years.” He underwent a time-dependent withdrawal reaction after admission. It was characterized by rebound insomnia, anxiety, craving, skin paresthesia, influenza-like symptoms, tonic-clonic-type seizures, and hallucinations. At the 1-year follow-up, he did not exhibit any remaining withdrawal symptoms. Discussion The acute cessation of overdosage zolpidem use causes a series of withdrawal symptoms that manifest in chronological order. Additionally, long-term benzodiazepine exposure has potential influences on zolpidem dependence/tolerance. However, patients with a history of abuse or dependence, or mental disorders seem to be at risk of drug abuse. Clinicians should be alert to the potential for zolpidem dependence and addiction. Once the acute cessation of overdosage zolpidem use occurs, the potential of the withdrawal reaction needs to be considered and addressed properly.

To compare the clinical feasibility and oncological outcome of different surgical techniques for inguinal lymphadenectomy (ILND) in patients suffering from penile cancer. This study included data from 109 cN 0–2 patients diagnosed with penile cancer who received ILND. 80 laparoscopic ILND were performed on 40 patients, while 138 open surgeries were performed on 69 patients. Perioperative complications and prognosis were compared between different surgical techniques. Compared with the open surgery group, the laparoscopy group had a shorter hospital stay (8.88 ± 7.86 days vs. 13.94 ± 10.09 days, P = 0.004), and a lower wound healing delay rate (8.75% vs. 22.46%, P = 0.017), but also had longer drainage time (10.91 ± 9.66 vs. 8.70 ± 4.62, P = 0.002). There were no significant differences in terms of other intraoperative parameters, complications, and survival between open and laparoscopic group. Compared with saphenous vein ligated subgroup, preserved subgroup showed no significant reducing of complication rate. There was no significant difference among complication between different open surgery subgroup. Immediate ILND showed no prognostic advantage over delayed ILND regardless of clinical lymph node status. Compared with open surgery, the minimally invasive ILND technique has similar oncological efficiency and a lower complication rate. Saphenous vein preservation has limited value in reducing complications. Delayed lymphadenectomy might be a more reasonable option for ILND.

BackgroundTo better understand the characteristics, and survival outcomes of synchronous renal cell carcinoma (RCC) and urothelial carcinoma (UC), we described and analyzed the clinical features, factors, and prognosis of patients with synchronous RCC and UC using a large population-based database.MethodsWithin the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016), we identified patient with concurrent RCC and UC at initial diagnosis. Their clinicopathological features and prognosis were evaluated. A logistic regression model was used to examine risk factors for the occurrence of concomitant RCC and UC, and Kaplan-Meier survival curves were used to estimate overall survival.ResultsA total of 61,454 RCC patients were identified from the SEER database, 704 (1.1%) patients presented with synchronous RCC and UC. Among these patients, concurrent bladder tumors (566/704) are more common. Subsequently, subgroup analysis based on the location of UC indicated that patients with concurrent RCC and upper tract urothelial carcinoma (UTUC) had unfavorable UC characteristics (higher tumor stage and grade), compared with patients with concomitant bladder cancer. An increased risk of concurrent UC was observed among older age, male sex, and white race. Meanwhile, papillary RCC histology [odds ratio (OR) 3.23; 95% confidence interval (CI) 2.13–4.90], and smaller tumor (OR 6.63; 95% CI 4.46–9.87) were independent risk factors for concomitant UTUC. In addition, we found that synchronous RCC and UTUC was associated with worse survival by using Kaplan-Meier and multivariable analysis [hazard ratio (HR) 2.36, 95% CI 1.89–2.95]. However, concomitant bladder cancer did not affect survival outcomes of patients with RCC (HR 1.00, 95% CI 0.86–1.17).ConclusionWe found that synchronous concurrent RCC and UC is relatively uncommon and mostly located in the bladder. Older age, male sex, and white race increase the risk of synchronous RCC and UC. Meanwhile, patients with papillary RCC histology, and smaller tumors are more likely to have concomitant RCC and UTUC. Furthermore, our findings suggest that synchronous RCC and UTUC has a worse prognosis, while, concomitant bladder tumor did not affect the oncological outcomes of RCC.

BACKGROUND:Alcohol dependence is a mental disorder with a high relapse rate. However, specific neuroimaging biomarkers have not been determined for alcohol dependence and its relapse. We conducted data-driven research to investigate resting-state functional magnetic resonance imaging (rs-fMRI) during early abstinence from alcohol dependence and its potential ability to predict relapse.METHODS:Participants included 68 alcohol-dependent patients and 68 healthy controls (HCs). The regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) were compared between the alcohol dependence group and the HCs and between the relapse group and the nonrelapse group. The brain regions that presented significantly different ReHo and/or fALFF between the alcohol-dependent patients and HCs and/or between the relapsed and nonrelapsed patients were selected as the seeds to calculate the functional connectivities (FCs).RESULTS:During a 6-month follow-up period, 52.24% of alcohol-dependent patients relapsed. A regression model for differentiating alcohol-dependent patients and HCs showed that reductions in ReHo in the left postcentral region, fALFF in the right fusiform region, and FC in the right fusiform region to the right middle cingulum were independently associated with alcohol dependence, with an area under the receiver operating characteristic curve (AUC) of 0.841. The baseline FC of the left precentral to the left cerebellum of the relapse group was significantly lower than that of the nonrelapse group. The AUC of this FC to predict relapse was 0.774.CONCLUSIONS:Our findings contribute to advancing research on the neurobiological etiology and predictive biomarkers for relapse associated with alcohol dependence.